{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T07:05:48Z","timestamp":1782371148144,"version":"3.54.5"},"reference-count":53,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2019,10,10]],"date-time":"2019-10-10T00:00:00Z","timestamp":1570665600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["R01AR053897"],"award-info":[{"award-number":["R01AR053897"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"name":"A Foundation for Building Strength","award":["NA"],"award-info":[{"award-number":["NA"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Respiratory failure due to diaphragm dysfunction is considered a main cause of death in nemaline myopathy (NM) and we studied both isometric force and isotonic shortening of diaphragm muscle in a mouse model of nebulin-based NM (Neb cKO). A large contractile deficit was found in nebulin-deficient intact muscle that is frequency dependent, with the largest deficits at low\u2013intermediate stimulation frequencies (e.g., a deficit of 72% at a stimulation frequency of 20 Hz). The effect of the fast skeletal muscle troponin activator (FSTA) tirasemtiv on force was examined. Tirasemtiv had a negligible effect at maximal stimulation frequencies, but greatly reduced the force deficit of the diaphragm at sub-maximal stimulation levels with an effect that was largest in Neb cKO diaphragm. As a result, the force deficit of Neb cKO diaphragm fell (from 72% to 29% at 20 Hz). Similar effects were found in in vivo experiments on the nerve-stimulated gastrocnemius muscle complex. Load-clamp experiments on diaphragm muscle showed that tirasemtiv increased the shortening velocity, and reduced the deficit in mechanical power by 33%. Thus, tirasemtiv significantly improves muscle function in a mouse model of nebulin-based nemaline myopathy.<\/jats:p>","DOI":"10.3390\/ijms20205008","type":"journal-article","created":{"date-parts":[[2019,10,11]],"date-time":"2019-10-11T03:07:11Z","timestamp":1570763231000},"page":"5008","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Functional Characterization of the Intact Diaphragm in a Nebulin-Based Nemaline Myopathy (NM) Model-Effects of the Fast Skeletal Muscle Troponin Activator tirasemtiv"],"prefix":"10.3390","volume":"20","author":[{"given":"Eun-Jeong","family":"Lee","sequence":"first","affiliation":[{"name":"Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85721, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin","family":"Kolb","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85721, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darren T.","family":"Hwee","sequence":"additional","affiliation":[{"name":"Research and Early Development, Cytokinetics, Inc., South San Francisco, CA 94080, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fady I.","family":"Malik","sequence":"additional","affiliation":[{"name":"Research and Early Development, Cytokinetics, Inc., South San Francisco, CA 94080, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9516-407X","authenticated-orcid":false,"given":"Henk L.","family":"Granzier","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85721, USA"},{"name":"Medical Research Building, RM 325, 1656 E Mabel St, Tucson, AZ 85721, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,10,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1016\/S0960-8966(99)00061-9","article-title":"Clinical and genetic heterogeneity in autosomal recessive nemaline myopathy","volume":"9","author":"Pelin","year":"1999","journal-title":"Neuromuscul. 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